Cardiovascular disease remains a leading cause of death worldwide, however therapeutic options remain limited. New treatment guidelines released in 2013 by the American Heart Association and American College of Cardiology emphasize reducing low density lipoprotein cholesterol (LDL-C) with statins and simultaneously highlight the absence of additional therapeutic options that have been validated by randomized clinical trials. Nevertheless, the risk of major cardiac events for patients on statins remains hig. Epidemiological studies have demonstrated a strong inverse correlation between high density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease providing support for the potential benefit of raising HDL-C. Negative results from clinical trials designed to test the beneficial effects of raising HDL-C, however, have raised concerns about this approach. Recent studies suggest that HDL function, particularly the ability of HDL particles to act as acceptors fo cholesterol transferred from peripheral macrophages, may be a more accurate predictor of cardiovascular disease than HDL-C levels. Transfer of cholesterol from macrophages to HDL serves as the first step in the process of reverse cholesterol transport (RCT) that ultimately transports cholesterol out of the body. The factors that regulate RCT throughout the body and the potential of such factors for therapeutic targeting remain to be determined. The liver X receptors LXRs are ligand-activated transcription factors that function as important regulators of cholesterol metabolism. Our preliminary experiments suggest that LXRs modulate HDL cholesterol acceptor activity by controlling the lipid composition of HDL. We hypothesize that direct regulation of genes encoding lipid remodeling enzymes such as the phospholipid transfer protein (PLTP) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) contributes to beneficial effects of LXR activation on HDL function. These studies should identify potential new approaches for therapeutic targeting of the RCT pathway. We have also uncovered an unexpected role for adipose tissue in the RCT pathway and we propose that the ability of adipose tissue to contribute to RCT is impaired in pathological settings such as obesity leading to decreased excretion of cholesterol and promoting cardiovascular disease.